New strategy for suppressing the growth of lung cancer cells harboring mutations in the ATP‐binding region of EGFR by targeting the molecular motor MYO1D

Abbreviations EGFR epidermal growth factor receptor NSCLC nonsmall cell lung cancer RTK receptor tyrosine kinase TIRF total internal reflection fluorescence TKI tyrosine kinase inhibitor Dear Editor, In this study, we describe that the molecular motor MYO1D holds both wild-type and mutant EGFRs in the plasma membrane via interaction of MYO1D with a C-terminal portion of the kinase domain (C-terminal substrate-binding lobe or C-lobe) that does not contain the ATP-binding region. The main challenge during EGFR-targeted therapy in nonsmall cell lung cancer (NSCLC) is the acquisition of resistance to EGFR-TKIs.1 Mechanisms of therapeutic resistance include mutations of the kinase domain at the T790M or C797S codon that interfere with TKI access to the active site, which is difficult to treat with standard therapeutic options.2,3 The EGFR (ErbB1) and ErbB2 pathways are functionally linked and pivotal in the progression of NSCLC.1 Overexpression of ErbB2 has been reported in about 20% of lung cancers in which mutant ErbB2 is more potent than the wild type in promoting tumorigenicity.4,5 Thus, combined inhibition of ErbB receptors could prevent a molecular feedback loop responsible for acquired resistance to existing anti-ErbB agents.6,7 To this aim, a new strategy can be considered: a single multitargeted agent and a new class of anti-ErbB agent with a different molecular mechanism. Previously, we provided the first evidence that the molecular motor MYO1D helps to maintain cell-surface ErbB receptor levels (except ErbB3) by holding the receptor to the plasma membrane.8 Here, we evaluated whether MYO1D also holds mutant EGFRs on the NSCLC cell surface and whether blockade of MYO1D function affects the proliferation and survival of NSCLC cells with variable resistance to existing anti-ErbB agents. [...]EGFR was reduced after knockdown of MYO1D in osimertinib-sensitive H1975 cells harboring L858R/T790M, and osimertinib-resistant H1975/OR cells (Figure 1C), which acquired resistance to osimertinib through the epithelial-to-mesenchymal transition.10 Moreover, ErbB2 expression was decreased after knockdown of MYO1D in NCI-H1781 lung cancer cells (Figure 1D) expressing wild-type EGFR and mutant ErbB2 containing a Val-Cys insertion at G776 in exon 20 of the ErbB2 gene.